(1) Field of the Invention
The present invention relates to a process for producing daunomycin and baumycins, and more particularly, the present invention relates to a process for producing anthracycline glycosides of the general formula I: ##STR1## wherein
R represents a hydrogen atom or the following structure: ##STR2## by microbial conversion of anthracyclinones having the general formula II: ##STR3## wherein
R.sup.1 represents a hydrogen atom or a hydroxyl group, using daunomycin- or baumycin-producing microorganisms and mutants therefrom.
(2) Description of the Prior Art
A number of anthracycline glycosides have been described in prior literature. Among them, daunomycin and adriamycin are particularly being watched with keen interest by those in the field of cancer chemotherapy and have already been applied clinically for human cancers. Preparation of adriamycin by fermentation of Streptomyces peucetius var. caesius is disclosed in U.S. Pat. No. 3,590,028. Chemical conversion of daunomycin to adriamycin is taught in U.S. Pat. No. 3,803,124. Daunomycin produced by fermentation of S. peucetius in U.K. Pat. No. 1,003,383 is the same as Rhone-Poulenc's 13057RP (See U.K. Pat. Nos. 985,598, 1,188,262 and 1,241,750 and U.S. Pat. No. 3,616,242) and dihydrodaunomycin is disclosed in U.S. Pat. No. 3,686,163.
Rhodomycinone, isorhodomycinone and rhodomycins-related antibiotics are described in Chem. Ber. 88, 1792-1818 (1955); Chem. Ber. 101, 1341-1348 (1968); J. Med. Chem. 20, 957-960 (1977); Pharmacie 27, 782-789 (1972); Zeit. Allg. Mikrobiol., 14, 551-558 (1974); Tetrahed. Lett. No. 38, 3699-3702 (1973); Folia Microbiol., 24, 293-295 (1979) and J. Antibiotics, 32, 420 (1979).
Aklavinone, aclacinomycins and baumycins are disclosed in U.S. Pat. No. 3,988,315, and by Oki et al in J. Antibiotics 28, 830 (1975), 32, 791-812 (1979), 30, 619-621 (1977), and 30, 622-624 (1977), and in Jap. J. Antibiotics, 30, S-70-84 (1977).
For further illustrative and summary disclosures of anthracycline antibiotics, see Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-Chief, University Park Press, State College, Pa., U.S.A. (1967). The textbook, Antibiotics, Volume 1, Mechanism of Action, edited by D. Gottlieb and P. D. Shaw, Springer-Verlag, New York, Inc., N.Y. (1967) on pages 190-210 contains a review by A. DiMarco entitled Daunomycin and Related Antibiotics.
In the continuation of studies on biosynthesis of anthracycline glycosides, particularly daunomycin and adriamycin, the present inventors discovered a new biosynthetic pathway to daunomycin and have developed unique process for producing daunomycin, baumycins and their related anthracycline glycosides with high yield from biologically inactive anthracyclinones by microbial glycosidation. As a result, the present inventors found that daunomycin and related-anthracycline-producing microorganisms, for example, Streptomyces coeruleorubidus ME130-A4 (FERM-P 3540, ATCC 13740), Streptomyces peucetius subsp. carneus ATCC 21354, Streptomyces peucetius NRRL B-3826 (FERM-P 3989) and mutants therefrom, did not produce daunomycin and baumycins from daunomycinone, but did from aklavinone and .epsilon.-rhodomycinone by microbial glycosidation. The inventors, thus, first established that a biologically inactive anthracyclinone aglycone added exogenously to the culture medium is preferably converted to biologically potent anthracyclines by the use of microorganisms.